Macrophages play a pivotal role in several immunobiological reactions. Our research is concerned with those macrophages associated with murine sarcomas and how they may influence the behavior of the tumor. We will be using the cytotoxic drug, cyclophosphamide (CY), as a probing agent to induce two distinctive reactions in which macrophages may play an important role. The first is tumor regression, induced by CY injection, and the second is tumor recurrence that follows in nearly all cases after CY-induced regression. The objective is to test three hypotheses that may not be mutually exclusive: (1) that tumor-associated macrophages (TAM) may preferentially eliminate cells damaged by the metabolites of CY and fail to destroy undamaged, tumorigenic cells; (2)\that TAM may directly stimulate the proliferation of residual tumorigenic cells or they may enhance their survival by abrogating antitumor effector mechanisms; and (3) that newly arrived tumor-associated monocytes may be responsible for the above effects rather than the more mature, resident TAM. Since our data indicate that TAM do not eliminate residual tumorigenic cells, experiments are currently under way to determine (a) whether the infusion of tumor-sensitized lymphocytes after CY treatment of mice results in permanent tumor regression and (b) the mechanism of action. Infused T cells were shown to consist of the Lyt-1+2+, Lyt-1+2- phenotypes. An analysis of the cellular composition of regressing tumors indicated that by day 10 after the combined treatment of CY and immune cells up to 50-60% of the cells were Thy-1+, of which 79-84% were Lyt-1+ and 66-71% Lyt-2+ indicating a mixture of Lyt-1+2+, Lyt-1+2- and Lyt-1-2+ phenotypes. Isolated T cells and macrophages were cytotoxic in vivo and in vitro. However, macrophage-mediated cytotoxicity was not dependent on the presence of Thy-1+ cells. Further investigation willconcentrate on the mechanism of cytotoxicity, the role of the donor T cells and whether the tumor-bearer's immune system can be utilized in place of immune cells from a donor.